2010 欧洲肿瘤医学会：弥漫大B淋巴瘤

Annals of Oncology 21 (Supplement 5): v172–v174, 2010 doi:10.1093/annonc/mdq203clinical practice guidelines Diffuse large B-cell non-Hodgkin’s lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up H. Tilly1 & M. Dreyling2 On behalf of the ESMO Guidelines Working Group* 1Department of Hematology, Centre Henri Becquerel, Rouen, France; 2Department of Medicine III, University Hospital Grosshadern, LMU Munich, Germany newly diagnosed diffuse large B-cell non-Hodgkin’s lymphoma incidence Diffuse large B-cell non-Hodgkin’s lymphoma (DLBCL) constitutes 30%–58% of non-Hodgkin’s lymphoma series. The crude incidence in the European Union is 3–4/100 000/year. The incidence increases with age from 0.3/100 000/year (35–39 years) to 26.6/100 000/year (80–84 years). diagnosis Diagnosis should be made on the basis of a surgical specimen/ excisional lymph node or extranodal tissue biopsy providing enough material for formalin-fixed samples. Core biopsies may be appropriate as the only diagnostic test in the rare patients requiring emergency treatment. Minimal immunohistochemistry (CD45, CD20 and CD3) is mandatory. The collection of fresh frozen material for molecular characterization is recommended although gene expression profiling remains investigational. To ensure adequate quality, processing by an experienced pathology institute has to be guaranteed. The histological report should give the diagnosis according to the current World Health Organization classification. staging and risk assessment A complete blood count, routine blood chemistry including lactate dehydrogenase (LDH) and uric acid as well as a screening test for human immunodeficiency virus and hepatitis B and C are required. Protein electrophoresis is recommended. Patients amenable to curative therapy should have at least a computed tomography (CT) scan of the chest and abdomen, as well as a bone marrow aspirate and biopsy. A diagnostic spinal tap should be considered in high-risk patients [V, D]. [18F]deoxyglucose positron emission tomography (FDG- PET) scanning is strongly recommended to better delineate the extent of the disease and with a view to the evaluation of treatment response according to the revised criteria. Performance status and cardiac function (left ventricular ejection fraction) should be assessed before treatment. The staging is established according to the Ann Arbor system [I, A]. For prognostic purposes, IPI and age-adapted IPI (aa- IPI) should be calculated [I, A]. treatment Treatment strategies should be stratified according to age, age- adapted IPI and feasibility of dose-intensified approaches. Whenever available, the inclusion in a clinical trial should be considered. In cases with high tumour load, special precautions are required to avoid tumour lysis syndrome. Dose reductions due to hematological toxicity should be avoided. Febrile neutropenia justifies prophylactic use of hematopoietic growth factors in patients treated with curative intent. young low- and low–intermediate-risk patients (aaIPI £1). Six to eight cycles of combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) treatment combined with six to eight doses of rituximab given every 21 days is the current standard for CD20+ diffuse large-cell non-Hodgkin’s lymphoma of all stages [I, A]. Dose-dense/dose-intensive regimens remain experimental. Consolidation by radiotherapy to initial sites has no clear proven benefit [I, A]. young high- and high–intermediate-risk patients (aaIPI ‡2). There is no current standard with sufficient efficacy. Thus, especially this patient population should be treated preferably in clinical trials. However, six to eight cycles of chemotherapy with CHOP combined with eight doses of rituximab given every 21 days are most frequently applied [I, A]. Dose-dense (R-CHOP-14; R-CHOP given every 2 weeks) *Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L. Taddei 4, CH-6962 Viganello-Lugano, Switzerland; E-mail: clinicalrecommendations@esmo.org Approved by the ESMO Guidelines Working Group: February 2002, last update January 2010. This publication supercedes the previously published version—Ann Oncol 2009; 20 (Suppl 4): iv110–iv112. Conflict of interest: Dr Tilly has reported no conflicts of interest; Prof. Dreyling has reported that he has received research support from Roche and that he is a member of its advisory board. ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org at St Jude Childrens Research Hospital on Septem ber 4, 2010 a n n o n c.o xfordjournals.org D ow nloaded from or dose-intensive (like R-ACVBP; rituximab, doxorubicin, vindesine, cyclophosphamide, bleomycin, prednisolone given every 2 weeks followed by sequential consolidation) regimens could also be proposed. High-dose chemotherapy with stem- cell transplantation as consolidation treatment after immunochemotherapy remains experimental in first-line therapy but recent phase II trials have shown promising results. Consolidation by radiotherapy to sites of bulky disease has proved to be of no benefit [III, C]. The role of radiotherapy in partial remission remains to be established in patients treated with rituximab abd evaluated with PET. patients aged 60–80 years. Eight cycles of combination chemotherapy with CHOP treatment combined with eight doses of rituximab given every 21 days is the current standard [I, A]. If rituximab-CHOP is given every 14 days, six cycles of CHOP with eight cycles of rituximab are sufficient. In patients with localized disease, consolidation by radiotherapy has proved to be of no benefit [I, A]. patients aged >80 years. R-CHOP treatment could usually be used until 80 years of age in fit patients. Small series have shown that the combination of rituximab with attenuated chemotherapy could induce complete remission and long survival in some very elderly patients. CNS prophylaxis. Patients with high–intermediate- and high- risk IPI, especially those with more than one extranodal site or elevated LDH are at higher risk of CNS relapse. CNS prophylaxis should be recommended in this population but intrathecal injections of methotrexate are probably not an optimal method. Whether some specific involvement sites such as paranasal sinus, upper neck or bone marrow should receive prophylaxis remains to be established. Testicular lymphoma must receive CNS prophylaxis. some extra-nodal DLBCLs require special consideration. Treatment of primary DLBCL of the central nervous system must contain high-dose methotrexate. Addition of high-dose cytarabine seems to improve complete remission rate and outcome. CNS irradiation is usually associated. Primary DLBCL of the testis is characterized by an increased risk of extranodal relapse. CNS prophylaxis is mandatory. Prophylactic irradiation of the contralateral testis should be considered in localized disease. Primary mediastinal large B-cell lymphoma (PMBL) is probably a distinct entity. R-CHOP 21 is not established as the definitive treatment option and radiotherapy remains controversial. response evaluation Abnormal radiological tests at baseline should be repeated after three to four cycles and after the last cycle of treatment. Bone marrow aspirate and biopsy should only be repeated at the end of treatment if initially involved. PET is highly recommended for post-treatment assessment to define complete remission according to the revised criteria of response. In the case of therapeutic consequences a histological confirmation of PET positivity at this time is strongly recommended. Early PET, performed after one to four cycles of treatment, could be predictive of clinical outcome but its results should not lead to treatment change outside of a clinical trial. follow-up History and physical examination every 3 months for 1 year, every 6 months for 2 more years, and then once a year with attention to development of secondary tumours or other long- term side-effects of chemotherapy [V, D]. Blood count and LDH at 3, 6, 12 and 24 months, then only as needed for evaluation of suspicious symptoms or clinical findings in those patients suitable for further therapy [V, D]. Minimal adequate radiological examinations at 6, 12 and 24 months after end of treatment, by CT scan is usual practice but there is no definitive evidence that routine imaging in patients in complete remission provides any outcome advantage. Routine surveillance with PET scan is not recommended. High- risk patients with curative options may potentially mandate more frequent controls. relapsed and refractory DLBCL incidence Overall, >30% of DLBCL will ultimately relapse. The incidence in the European Union is therefore estimated to be�1/100 000/ year. diagnosis Histological verification should be obtained whenever possible, and is mandatory in relapses >12 months after the initial diagnosis, especially in order to ensure CD20 positivity. Image- guided core biopsy may be appropriate in this context. staging and risk assessment Patients still amenable to curative therapy should have the same examinations as at first diagnosis. treatment The following recommendations apply to patients with adequate, rituximab-associated anthracycline-containing first- line therapy. In suitable patients with adequate performance status (no major organ dysfunction, age <65–70 years) a salvage regimen with association of rituximab and chemotherapy followed in responsive patients by high-dose treatment with stem-cell support is recommended [II, A]. Salvage regimens such as R- DHAP (rituximab, cisplatin, cytosine–arabinoside, dexamethasone) or R-ICE (rituximab, ifosfamide, carboplatin, etoposide) may be adequate. The choice of the high-dose regimen depends on local experience; BEAM (carmustine, etoposide, cytosine–arabinoside and melphalan) is the more frequently used. Additional involved-field radiation or iceberg radiation may be used especially in the few cases with limited stage disease, but it has been never evaluated in controlled trials. Patients not suitable for high-dose therapy may be treated with the same or other salvage regimens such as R-GEMOX (rituximab, gemcitabine, oxaliplatin), which may be combined with involved-field radiotherapy. Annals of Oncology clinical practice guidelines Volume 21 | Supplement 5 | May 2010 doi:10.1093/annonc/mdq203 | v173 at St Jude Childrens Research Hospital on Septem ber 4, 2010 a n n o n c.o xfordjournals.org D ow nloaded from response evaluation Response criteria are identical to those of first-line treatment evaluation. An evaluation should be performed after three to four cycles of salvage regimen (before high-dose treatment) and after the end of all therapy. Results of PET before high-dose treatment are correlated with clinical outcome. follow-up Follow-up of patients in second response could be the same as first response. note Levels of Evidence [I–V] and Grades of Recommendation [A– D] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justified standard clinical practice by the experts and the ESMO faculty. literature 1. Morgan G, Vornanen M, Puitinen J et al. Changing trends in the incidence of non-Hodgkin’s lymphoma in Europe. Biomed Study Group. Ann Oncol 1997; 8 (Suppl 2): 49–54. 2. Swerdlow SH, Campo E, Harris NL et al. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC; 2008. 3. Cheson BD, Pfistner B, Juweid ME et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007; 25: 1–8. 4. Shipp M, Harrington D, Anderson J et al. A predictive model for aggressive non- Hodgkin’s lymphoma. N Engl J Med 1993; 329: 987–994. 5. Pfreundschuh MG, Trumper L, Osterborg A et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good- prognosis diffuse large B-cell lymphoma—a randomized controlled trial by the Mab Thera International Trial (MinT) Group. Early stopping after the first interim analysis. Lancet Oncol 2006; 7: 379–391. 6. Reyes F, Lepage E, Ganem G et al. ACVBP versus CHOP plus radiotherapy in localized aggresive lymphoma. N Engl J Med 2005; 352: 1197–1205. 7. Tarella C, Zanni M, Di Nicola M et al. Prolonged survival in poor-risk diffuse large B-cell lymphoma following front-line treatment with rituximab-supplemented, early-intensified with multiple autologous hematopoietic stem cell support: a multicenter study by GITIL (Gruppo Italiano Terapie Innovative nei Linfomi). Leukemia 2007; 21: 1802–1811. 8. Vitolo U, Chiappella A, Angelucci E et al. Dose-dense and high-dose chemotherapy plus rituximab with autologous stem cell transplantation for primary treatment of diffuse large B-cell lymphoma with a poor prognosis: a phase II multicenter study. Haematologica 2009; 94: 1250–1258. 9. Moser EC, Kluin-Nelemans HC, Carde P et al. Impact of involved field radiotherapy in partial response after doxorubicin-based chemotherapy for advanced aggressive non-Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys 2006; 66: 1168–1177. 10. Coiffier B, Lepage E, Briere J et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002; 346: 235–242. 11. Pfreundschuh M, Schubert J, Ziepert M et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B- cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 2008; 9: 105–116. 12. Bonnet C, Fillet G, Mounier N et al. CHOP alone compared with CHOP plus radiotherapy for localized aggressive lymphoma in elderly patients: a study of the Groupe d’Etudes des Lymphomes de l’Adulte. J Clin Oncol 2007; 25: 1–6. 13. Italiano A, Jardin F, Peyrade F et al. Adapted CHOP plus rituximab in non- Hodgkin’s lymphoma in patients over 80 years old. Haematologica 2005; 90: 1281–1283. 14. Feugier P, Virion JM, Tilly H et al. Incidence and risk factors for central nervous system occurrence in elderly patients with diffuse large-B-cell lymphoma: influence of rituximab. Ann Oncol 2004; 15: 129–133. 15. Boehme V, Schmitz N, Zeynalova S et al. CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: an analysis of patients treated in the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Blood 2009; 113: 3896–3902. 16. Barosi G, Carella A, Lazzarino M et al. Italian Society of Experimental Hematology; Italian Group for Bone Marrow Transplantation. Management of nodal diffuse large B-cell lymphomas: practice guidelines from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation. Haematologica 2006; 91: 96–103. 17. Ferreri AJ, Reni M, Foppoli M et al. High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet 2009; 374: 1512–1520. 18. Zucca E, Conconi A, Mughal TI et al. Patterns of outcome and prognostic factors in primary large-cell lymphoma of the testis in a survey by the International Extranodal Lymphoma Study Group. J Clin Oncol 2003; 21: 20–27. 19. Martelli M, Ferreri AJ, Johnson P. Primary mediastinal large B-cell lymphoma. Crit Rev Oncol Hematol 2008; 68: 256–263. 20. Armitage JO, Loberiza FR. Is there a place for routine imaging for patients in complete remission from aggressive lymphoma? Ann Oncol 2006; 17: 883–884. 21. Philip T, Guglielmi C, Hagenbeek A et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 1995; 333: 1540–1545. 22. Kewalramani T, Zelenetz AD, Nimer SD et al. Rituximab and ICE as secondline therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B cell lymphoma. Blood 2004; 103: 3684–3688. 23. Khouri IF, Saliba RM, Hosing C et al. Concurrent administration of high-dose rituximab before and after autologous stem-cell transplantation for relapsed aggressive B-cell non-Hodgkin’s lymphomas. J Clin Oncol 2005; 23: 2240–2247. 24. Horwitz SM, Negrin RS, Blume KG et al. Rituximab as adjuvant to high-dose therapy and autologous hematopoietic cell transplantation for aggressive non- Hodgkin lymphoma. Blood 2004; 103: 777–783. 25. Hagberg H, Gisselbrecht C. CORAL study group. Randomised phase III study of R-ICE versus R-DHAP in relapsed patients with CD20 diffuse large B-cell lymphoma (DLBCL) followed by high-dose therapy and a second randomisation to maintenance treatment with rituximab or not: an update of the CORAL study. Ann Oncol 2006; 17 (Suppl 4): 31–32. 26. El Gnaoui T, Dupuis J, Belhadj K et al. Rituximab, gemcitabine and oxaliplatin: an effective salvage regimen for patients with relapsed or refractory B-cell lymphoma not candidates for high-dose therapy. Ann Oncol 2007; 18: 1363–1368. clinical practice guidelines Annals of Oncology v174 | Tilly & Dreyling Volume 21 | Supplement 5 | May 2010 at St Jude Childrens Research Hospital on Septem ber 4, 2010 a n n o n c.o xfordjournals.org D ow nloaded from